Voltage-gated sodium channels have a relevant role in the initiation and propagation of electrical signalling in excitable cells. Genetic studies have proven that inherited disorders like cardiac arrhythmias, epilepsy and loss or gain of pain sensation could be linked to mutations of genes that encode Nav subtypes. (Nardi A. et al, Chem Med Chem, 2012, 7, 1-30).
There are nine subtypes of voltage-gated sodium channels in humans. Although they are very similar in sequence, different sodium channel subtypes have important and diverse physiological roles. Nav1.1, Nav1.2, and Nav1.3 are highly expressed in the central nervous system. Nav1.4 is primarily found in skeletal muscle and Nav1.5 is expressed mainly in the cardiac muscle. Nav1.6 is a widely expressed sodium channel and it can be found throughout the central and the peripheral nervous system. Nav1.7, Nav1.8 and Nav1.9 are found predominantly in peripheral sympathetic and sensory neurons.
Most of the small Nav1.7 inhibitors are known to bind a region of the channel in the inner vestibule of the pore on transmembrane S6 domain IV which is highly conserved between subtypes. However, it is possible to find selective Nav1.7 inhibitors.
A selective Nav1.7 would be highly desirable to avoid undesired adverse effects observed with existing non-selective Nav inhibitors such as Lidocaine which have a limited therapeutic window.
Particularly, finding selectivity of Nav1.7 with respect to Nav1.5 would be desirable to avoid any cardiovascular side effects.
State dependent inhibitors are thought to stabilise an inactivated conformation of the channel which is adopted rapidly after the channel opens. This inactivated state provides a refractory period before the channel returns to its resting state ready to be reactivated. State dependent inhibition is proposed to reflect an allosteric mechanism by which the drug receptor site is in the low-affinity conformation when the channel is at rest and converts into a high-affinity conformation when the channel is open or inactivated. This ability for sodium channels to adopt different conformations depending on the voltage would increase therapeutic index by enhancing functional selectivity as in healthy tissues sodium channels mostly reside in the resting state whereas inactivated state has a greater relevance in diseased tissue. (Priest B. T. et al, Curr. Top. Med. Chem. 2008, 3, 121-143, Ragsdale D. S., Brain Res. Brain Res. Rev. 1998, 26, 16-28, Yanagidate F., Exp. Pharmacol. 2007, 95-127).
Several studies relate gain-of-function mutations of the gene that encodes Nav1.7 to pain whereas loss-of-function mutations in this gene lead to an indifference to pain (Dib-Hajj, S. D et al, Annu. Rev. Neurosci. 2010, 33, 325-347). Additional studies have linked Nav1.7 to cough reflex (Muroi, Y. et al, J. Physiol. 2011, 589, 5663-5676).
Some modulators of voltage gated sodium channels in particular Nav1.7 were described in WO 2012/007861 and WO 2012/095781.
Other indazole and pyrazolo derivatives were described in the documents US 2004/235892 and US 2010/113415, although these compounds are useful as a modulators of tyrosin kinases.
Nav1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, such as pain, including but not limited to acute pain, chronic pain, inflammatory pain, visceral pain, nociceptive pain, neuropathic pain, postherpethic pain, trigeminal neuralgia, diabetic neuropathy, chronic back pain, chronic pelvic pain, pain resulting from cancer and chemotherapy, migraine, idiopathic cough, chronic cough or cough related to respiratory diseases, respiratory diseases, itch, dermatological diseases, epilepsy, squizophrenia and bipolar disorder. They can also be potentially used as analgesic and anaesthetic drugs.
We have now discovered novel aminoindazolyl derivative compounds as potent state dependent and selective Nav1.7 inhibitors.